Solid-phase preparation of [18f] fluorohaloalkanes

ABSTRACT

The invention relates to a process for the production of an [ 18 F]fluorohaloalkane which comprises treatment of a solid support-bound precursor of formula (I): SOLID SUPPORT-LINKER-SO 2 —O—(CH 2 ) n X (I) wherein n is an integer of from (1) to (7) and X is chloro, bromo or iodo; with  18 F −  to produce the [ 18 F]fluorohaloalkane of formula (II)  18 F—(CH 2 ) n X (II) wherein n and X are as defined for the compound of formula (I), optionally followed by (i) removal of excess  18 F − , for example by ion-exchange chromatography; and/or (ii) removal of organic solvent.

The present invention relates to a process for the preparation offluorohaloalkane compounds such as [¹⁸F]bromofluoromethane.[¹⁸F]Fluorohaloalkanes are important reagents for performing O—, N—, andS—[¹⁸F]fluoroalkylations and are commonly used to radiolabelradioligands for use in positron emission tomography (PET) studies.

[¹⁸F]Fluorohaloalkanes have previously been prepared by nucleophilicdisplacement, by [¹⁸F]F⁻, of a leaving group from a suitable precursorcompound. Thus, for example Zhang et al, Applied Radiation and Isotopes57, 335-342 (2002), describes synthesis of [¹⁸F]fluoroethyl bromide bynucleophilic displacement of 2-trifluoromethanesulphonyloxy ethylbromidewith [¹⁸F]F⁻ and Seung-Jun et al Applied Radiation and Isotopes (1999),51, 293-7 describes an analogous synthesis of3-[¹⁸F]fluoropropylbromide. A similar method is described in Comagic etal Applied Radiation and Isotopes (2002), 56, 847-851 wherein2-bromo-1-[¹⁸F]fluoroethane is prepared by nucleophilic displacement of1,2-dibromoethane with [¹⁸F]F⁻. Solid-phase nucleophilic fluorinationmethods are described in co-pending International Patent ApplicationPCT/GB02/02505.

In view of the importance of [¹⁸F]fluorohaloalkanes as radiolabellingreagents, there exists the need for synthetic methods for theirpreparation in good radiochemical yield and in which isolation of theproduct is more readily achievable. Furthermore, there is also a needfor such synthetic methods which are amenable to automation.

In a first aspect, the invention provides a process for the productionof an [¹⁸F]fluorohaloalkane which comprises treatment of a solidsupport-bound precursor of formula (I):SOLID SUPPORT-LINKER-SO₂—O—(CH₂)_(n)X   (I)wherein n is an integer of from 1 to 7 and X is chloro, bromo, or iodo;with ¹⁸F⁻ to produce the [¹⁸F]fluorohaloalkane of formula (II)¹⁸F—(CH₂)_(n)—X   (II)wherein n and X are as defined for the compound of formula (I),optionally followed by

-   -   (i) removal of excess ¹⁸F⁻, for example by ion-exchange        chromatography; and/or    -   (ii) removal of organic solvent.

Preferably, in the compounds of formula (I) above, n is an integer of 1to 4, more preferably, 1 or 2. In the compounds of formula (I) above, Xis preferably bromo or iodo. Preferred [¹⁸F]fluorohaloalkanes of formula(II) prepared, include [¹⁸F]fluorobromomethane, [¹⁸F]fluoroiodomethane,[¹⁸F]fluorobromoethane, [¹⁸F9fluoroiodoethane, [¹⁸F]fluorobromopropane,and ¹⁸F]fluoroiodopropane.

As the [¹⁸F]fluorohaloalkane of formula (II) is removed from thesolid-phase into solution, all unreacted precursor remains bound to theresin and can be separated by simple filtration, thus obviating the needfor complicated purification, for example by HPLC. The[¹⁸F]fluorohaloalkane of formula (II) may be cleaned up by removal ofexcess F⁻, for example by ion-exchange chromatography and/or by removalof any organic solvent.

As shown in Scheme 1, the compound of formula (I) may be convenientlyprepared from any sulphonic acid functionalised commercially availableresin, such as Merrifield Resin, NovaSyn® TG Bromo Resin,(Bromomethyl)phenoxymethyl polystyrene, or Wang Resin which may bereacted with a chlorinating agent to give the corresponding sulphonylchloride resin. This may be carried out by treating the resin with, forexample, phosphorus pentachloride, phosphorus trichloride, oxalylchloride, or thionyl chloride, in an appropriate inert solvent such asdichloromethane, chloroform, or acetonitrile, and heating at elevatedtemperature for a period of time. The excess reagent may then be removedfrom the resin by washing with further portions of the inert solvent.The sulphonyl chloride resin may then be reacted with the alcoholanalogue of the tracer to produce the resin-bound precursor of formula(I). This may be carried out by treating the resin with a solution ofthe alcohol in an inert solvent such as chloroform, dichloromethane,acetonitrile, or tetrahydrofuran containing a non-nucleophilic solublebase such as sodium hydride or a trialkylamine, for exampletriethylamine or diusopropylethylamine. The reaction may be carried outat a temperature of 10 to 80° C., optimally at ambient temperature for aperiod of from around 1 to 24 hours. The excess alcohol and base maythen be removed from the solid support by washing with further portionsof an inert solvent such as chloroform, dichloromethane, ortetrahydrofuran. Alternatively, the LINKER may be attached to thehaloalkane, before being attached to the SOLID SUPPORT to form thecompound of formula (I), using analogous chemistry to that describedabove.

In the compounds of formula (I), the “SOLID SUPPORT” may be any suitablesolid-phase support which is insoluble in any solvents to be used in theprocess but to which the LINKER and/or haloalkane can be covalentlybound. Examples of suitable SOLID SUPPORT include polymers such aspolystyrene (which may be block grafted, for example with polyethyleneglycol), polyacrylamide, or polypropylene or glass or silicon coatedwith such a polymer. The solid support may be in the form of smalldiscrete particles such as beads or pins, or as a coating on the innersurface of a cartridge or on a microfabricated vessel.

In the compounds of formula (I), the “LINKER” may be any suitableorganic group which serves to space the reactive site sufficiently fromthe solid support structure so as to maximise reactivity. Suitably, theLINKER comprises zero to four aryl groups (suitably phenyl) and/or aC₁₋₁₆alkyl (suitably C₁₋₆alkyl) or C₁₋₁₆haloalkyl (suitablyC₁₋₆haloalkyl), typically C₁₋₁₆ fluoroalkyl (suitably C₁₋₆ fluoroalkyl), or C₁₋₁₆alkoxy or C₁₋₁₆haloalkoxy (suitably C₁₋₆alkoxy orC₁₋₆haloalkoxy) typically C₁₋₁₆fluoroalkoxy (suitably C₁₋₆fluoroalkoxy),and optionally one to four additional functional groups such as amide orsulphonamide groups. Examples of such linkers are well known to thoseskilled in the art of solid-phase chemistry, but include:

wherein at each occurrence, k is an integer of 0 to 3, n is an integerof 1 to 16, and R^(L) is hydrogen or C₁₋₆ alkyl.

Treatment of the compound of formula (I) with ¹⁸F⁻ may be effected bytreatment with any suitable source of ¹⁸F⁻, such as Na¹⁸F, K¹⁸F, Cs¹⁸F,tetraalkylammonium ¹⁸F fluoride, or tetraalkylphosphonium ¹⁸F fluoride.To increase the reactivity of the fluoride, a phase transfercatalyst-such as 4,7,13,16,21,24 hexaoxa-1,10-diazabicyclo[8,8,8]hexacosane may be added and the reaction performed in a non proticsolvent. These conditions give reactive fluoride ions. The treatmentwith ¹⁸F⁻ is suitably effected in the presence of a suitable organicsolvent such as acetonitrile, dimethylformamide, dimethylsulphoxide,tetrahydrofuran, dioxan, 1,2 dimethoxyethane, sulpholane,N-methylpyrolidinineone, at a non-extreme temperature, for example, 15°C. to 180° C., preferably at elevated temperature. On completion of thereaction, the [¹⁸F]fluorohaloalkane of formula (II) dissolved in thesolvent is conveniently separated from the solid-phase by filtration.

Any excess ¹⁸F⁻ may be removed from the solution of[¹⁸F]fluorohaloalkane by any suitable means, for example by ion-exchangechromatography or solid phase absorbents. Suitable ion-exchange resinsinclude BIO-RAD AG 1-X8 or Waters QMA and suitable solid phaseabsorbents include alumina. The excess ¹⁸F⁻ may be removed using suchsolid phases at room temperature in aprotic solvents.

Any organic solvent may be removed by any standard method such as byevaporation at elevated temperature in vacuo or by passing a stream ofinert gas such as nitrogen or argon over the solution.

According to a further aspect, the invention provides a process for theproduction of an [¹⁸F]fluorohaloalkane which comprises treatment of asolid support-bound precursor of formula (III):

wherein n and X are as defined for the compound of formula (I), and Y-is an anion (preferably trifluoromethylsulphonate (triflate) anion ortetraphenyl borate anion); with ¹⁸F⁻ to produce the[¹⁸F]fluorohaloalkane of formula (II)¹⁸F—(CH₂)_(n)—X   (II)wherein n and X are as defined for the compound of formula (III),optionally followed by

-   -   (i) removal of excess ¹⁸F⁻, for example by ion-exchange        chromatography; and/or    -   (ii) removal of organic solvent.

The compound of formula (III) may be conveniently prepared from afunctionalised commercially available resin such as a Merrifield Resinor Wang Resin. Suitably, a hydroxylodoaryl (such as an iodophenol)containing LINKER group is treated with an inorganic base, such ascesium carbonate and then added to the resin, pre-swollen with an inertsolvent, such as N,N-dimethylformamide and allowed to react at elevatedtemperature, for example 30 to 80° C. Excess reagents may be removed bywashing the resin with further inert solvent. The resultant iodophenolfunctionalised resin may then be treated with a source of acetate anions(such as actetic acid, acetic anhydride, or acetyl chloride) in thepresence of an oxidising agent, such as hydrogen peroxide to provide thecorresponding diacetoxy-iodophenyl functionalised resin. Thediacetoxy-iodophenyl functionalised resin may then be stirred in aninert solvent, such as dichloromethane, in the presence of acid such ashydrochloric acid, trifluoromethane sulphonic acid, or acetic acid at alow temperature, suitably −40° C. to 10° C. before addition of thefluorohaloalkane, suitably functionalised as a boronic acid or triorganotin (suitably trialkyl tin) derivative which may be coupled to the resinat a non-extreme temperature. As in previous steps, the desired compoundof formula (III) may be separated by filtration and washing with aninert solvent.

In the compound of formula (III), the LINKER is as defined above butsuitably comprises an aryl group (suitably phenyl) adjacent to the I⁺.Preferred examples include:

wherein each phenyl is optionally substituted by 1 to 4 groups selectedfrom C₁₋₆alkyl and C₁₋₆alkoxy, but is suitably unsubstituted.

Treatment of a compound of formula (III) with F⁻, preferred haloalkanesin formula (III), removal of excess F⁻ and any organic solvent are allsuitably as described for the compounds of formula (I) above.

The compounds of formula (I) and (III) are novel and thus form a furtheraspect of the present invention.

As described above, the advantages of such solid-phase processes forpreparation of [¹⁸F]fluorohaloalkanes include the relative speed of theprocess, simplified purification methods and ease of automation—all ofwhich mean that the processes are suitable for preparation of[¹⁸F]fluorohaloalkanes which can then be used to prepared ¹⁸F-labelledtracers for use in PET. Accordingly, the present invention provides aprocess for the preparation of a [¹⁸F]fluorohaloalkane of formula (II)for use in PET chemistry.

Conveniently, the solid support bound precursor of formula (I) or (III)could be provided as part of a kit to a radiopharmacy, PET centre, ornuclear medicine department. The kit may contain a cartridge which canbe plugged into a suitably adapted automated synthesiser. The cartridgemay contain, apart from the solid support-bound precursor, a column toremove unwanted fluoride ion, and an appropriate vessel connected so asto allow the reaction mixture to be evaporated and allow the product tobe formulated as required. The reagents and solvents and otherconsumables required for the synthesis may also be included togetherwith a compact disc carrying the software which allows the synthesiserto be operated in a way so as to meet the customers requirements forradioactive concentration, volumes, time of delivery etc.

Conveniently, all components of the kit are disposable to minimise thepossibilities of contamination between runs and may be sterile andquality assured.

The invention further provides a radiosynthesis kit for the preparationof an [¹⁸F]fluorohaloalkane for use in PET chemistry, which comprises:

-   -   (i) a vessel containing a compound of formula (I) or (III); and    -   (ii) means for eluting the vessel with a source of ¹⁸F⁻; and    -   (iii) an ion-exchange cartridge for removal of excess ¹⁸F⁻.

The invention further provides a cartridge for a radiosynthesis kit forthe preparation of an [¹⁸F]fluorohaloalkane for use in PET chemistrywhich comprises:

-   -   (i) a vessel containing a compound of formula (I) or (III); and    -   (ii) means for eluting the vessel with a source of ¹⁸F⁻.

The invention will now be illustrated by way of the, following Examples.

EXAMPLE 1

Synthesis of [¹⁸F]-fluorobromomethane

EXAMPLE 1(i)

Preparation of perfluorobutane-1,4-bis-sulphonylchloride

(Following the method of Weiming Qiu and Donald J. Burton Journal offluorine chemistry, 60 (1993) 93-100.)

The mixture of 1,4 diiodoperfluorobutane (I(CF₂)₄I) (24.14 g, 53.2mmol),sodium dithionite Na₂S₂O₄ (24 g, 117.2mmol) and sodium hydrogen sulphateNaHCO₃ (12.8 g, 152.4mmol) in water H₂O (36 ml)/Acetonitrile CH₃CN (36ml) was stirred at room temperature for 2 hours. It was filtered, andthe filtrate was concentrated under reduced pressure to remove theacetonitrile. To the residue was added H₂O (100 ml). The so obtainedsolution was vigorously stirred and treated with chlorine gas Cl₂ at 0°C. until the colour of I₂ disappeared. Dichloromethane CH₂Cl₂ (100 ml)was added and the mixture vigorously shaken. The organic phase wasseparated, and the aqueous phase was extracted with CH₂Cl₂. The combinedorganic phase was washed with water H₂O, brine, and dried with sodiumsulphate Na₂SO₄ and concentrated to afford a waxy yellow crystallinesolid. (15.4 g, 74%). Recrystallization from hexane afforded off-whiteneedles of perfluorobutane-1,4-bis-sulphonylchloride.

¹⁹F NMR (CDCl₃, CFCl₃ reference) δ: −104.4, −119.1.

EXAMPLE 1(ii)

Preparation of perfluorobutane-1,4-bis-sulphonate dipotassium salt

To the solution of potassium hydroxide KOH (9.8 g, 5eq) in water H₂0 (19ml) was added gradually perfluorobutane-1,4-bis-sulphonylchloride (14 g,35mmol) at 85° C.-90° C. with stirring. After the addition, the reactionwas continued for more 4 hours at the same temperature, and then it wascooled overnight. It was filtered and the solids was washed with alittle of cooled water and dried in vacuum to giveperfluorobutane-1,4-bis-sulphonate dipotassium salt

¹⁹F NMR (CD₃OD, CFCl₃ reference) δ: −114.00, −120.11.

EXAMPLE 1(iii)

Preparation of perfluorobutane-1,4-bis-sulphonic acid

(Following the method described in U.S. Pat. No. 4,329,478, Fred E.Behr.)

Perfluorobutane-1,4-bis-sulphonate dipotassium salt (15 g, 34.2mmol) wasdissolved in hot water (100 ml). It was added to an ion exchange columnof Amberlyst 15 resin, (40×4cm) which had been previously washed withexcess 6N HCl and rinsed with distilled water. The column was thenwashed slowly with distilled water, and the first 300 ml of aqueoussolution collected. The solution was concentrated in vacuum and theresidue was dried under reduced pressure at 80° C. to affordperfluorobutane-1,4-bis-sulphonic acid. (11.0 g, 30mmol, 88%)

¹H NMR (CDCl₃,) δ: 8.00

¹⁸F NMR (CDCl₃, CFCl₃ reference) δ: −114.7, −121.3.

EXAMPLE 1(iv)

Preparation of perfluorobutane-1,4-bis-sulphonic acid anhydride

(Following the method described in U.S. Pat. No. 4,329,478, Fred E.Behr.)

Perfluorobutane-1,4-bis-sulphonic acid (11.0 g, ˜30mmol) was mixed withP₂O₅ (40 g, ˜10eq) and sand. The mixture was heated to 140-180° C. anddistilled under reduced pressure with dry-ice cooling collector toafford crude product (5.12 g). Redistilation gives pureperfluorobutane-1,4-bis-sulphonic acid anhydride.

¹⁸F NMR (CDCl₃, CFCl₃ reference) δ: −105.7, −121.8.

EXAMPLE 1(v)

Synthesis of PS-4-(Benzyl-ethyl-sulfonamide)octafluoro-butane-1-sulfonicacid

To a portion of the polystyrene resin (Novabiochem, Novasyn resin) (202mg), which had previously been swollen in dichloromethane (2 ml) andthen suspended in a further aliquot of dichloromethane (2 ml) theperfluorobutyl-1,4-cyclic-sulfonic anyhydride (116 mg, 5Eq) was added.Following this di-isopropyethyl amine (0.174 ml) was added and thesuspension stirred overnight at room temperature. The solvent wasremoved by filtration and the resin washed with consecutive addition andfiltration of dichloromethane (5 ml), methanol (5 ml), DMF (5 ml), water(5 ml), methanol (5 ml), and dichloromethane (5 ml). The resulting resinwas then treated with NaOH (1M) in THF/water (2×2ml) before washing withconsecutive portions of methanol (5 ml), dichloromethane (5 ml) andmethanol (5 ml) again. The resin was then dried under high vacuum.

Gel Phase ¹⁹F NMR (referenced to CFCl₃,300K): δ−121.0, −114.8, −113.4

EXAMPLE 1(vi)

Synthesis of PS-4-(Benzyl-ethyl-sulfonamide)octafluoro-butane-1-sulfonylchloride

A portion of the resin prepared in the manner of Example 1(v) above isswollen with dichloromethane (2 ml) and then washed consecutively withHCl (1M) in THF/water (10×5 ml) to give the free sulphonic acid. Theresin is washed consecutively with dichloromethane, methanol and THFbefore drying under high vacuum.

The resin is then suspended in dichloromethane and to it is added inexcess a common chlorinating agent such as phosphorous pentachloride,phosphorus trichloride orthionyl chloride. The suspension is stirred for2 hours before filtration and then washing of the resin withdichloromethane and then THF.

EXAMPLE 1(vii)

Synthesis of Fluorobromomethane Precursor Resin

A solution of bromomethanol in THF is added to a portion of the resinprepared as described in Example 1(vi) above which has previously beenswollen in THF. To this is added a solution of potassium t-butoxide intetrahydrofuran and the suspension is stirred overnight. Afterfiltration the resin is washed consecutively with dichloromethane andTHF before drying under high vacuum.

EXAMPLE 1(viii)

Radiofluorination To Prepare [¹⁸F]-fluorobromomethane

To a portion of the resin (prepared as described in Example 1(vii)) heldin a cartridge is added a solution in dry acetonitrile of kryptofix,potassium carbonate and [¹⁸F]-fluoride. The suspension is heated to 85°C. for 10 minutes and then the solution is filtered off. The solution isthen passed onto a C₁₈ solid phase extraction cartridge and washed withwater to remove acetonitrile, kryptofix and potassium carbonate.Addition of more acetonitrile washes the radiofluorinated product of thecartridge into a solution of 0.1 M HCl. This solution is heated for 5minutes before neutralization and analysis.

1. A process for the production of an [¹⁸F]fluorohaloalkane whichcomprises treatment of a solid support-bound precursor of formula (I):SOLID SUPPORT-LINKER-SO₂—O—(CH₂)_(n)X   (I) wherein n is an integer offrom 1 to 7 and X is chloro, bromo or iodo; with ¹⁸F⁻ to produce the[¹⁸F]fluorohaloalkane of formula (II)¹⁸F—(CH₂)_(n)—X   (II) wherein n and X are as defined for the compoundof formula (I), optionally followed by (i) removal of excess ¹⁸F⁻, forexample by ion-exchange chromatography; and/or (ii) removal of organicsolvent.
 2. A process for the production of an [¹⁸F]fluorohaloalkaneaccording to claim 1 wherein n is an integer of 1 to 4, preferably 1 or2.
 3. A process for the production of an [¹⁸F]fluorohaloalkane accordingto claim 1 wherein the compound of formula (II) prepared is selectedfrom [¹⁸F]fluorobromomethane, [¹⁸F]fluoroiodomethane,[¹⁸F]fluorobromoethane, [¹⁸F]fluoroiodoethane, [¹⁸F]fluorobromopropane,and [¹⁸F]fluoroiodopropane
 4. A compound of formula (I) as defined inclaim 1:SOLID SUPPORT-LINKER-SO₂—O—(CH₂)_(n)X   (I) wherein n is an integer offrom 1 to 7 and X is chloro, bromo or iodo.
 5. A compound of formula (I)according to claim 4 wherein n is an integer of from 1 to 4, and ispreferably 1 or
 2. 6. A radiosynthesis kit for the preparation of an[¹⁸F]fluorohaloalkane for use in PET chemistry, which comprises: (i) avessel containing a compound of formula (I) as defined in claim 1; and(ii) means for eluting the vessel with a source of ¹⁸F⁻; and (iii) anion-exchange cartridge for removal of excess ¹⁸F⁻.
 7. A cartridge for aradiosynthesis kit which comprises: (i) a vessel containing a compoundof formula (I) as defined in claim 1; and (ii) means for eluting thevessel with a source of ¹⁸F⁻.